scholarly journals The Fine LINE: Methylation Drawing the Cancer Landscape

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Isabelle R. Miousse ◽  
Igor Koturbash
Keyword(s):  
Dna Methylation ◽  
Current Knowledge ◽  
Methylation Status ◽  
Disease Free Survival ◽  
Disease Stage ◽  
Aberrant Expression ◽  
Free Survival ◽  
Clinical Biomarkers ◽  
Line Methylation

LINE-1 (L1) is the most abundant mammalian transposable element that comprises nearly 20% of the genome, and nearly half of the mammalian genome has stemmed from L1-mediated mobilization. Expression and retrotransposition of L1 are suppressed by complex mechanisms, where the key role belongs to DNA methylation. Alterations in L1 methylation may lead to aberrant expression of L1 and have been described in numerous diseases. Accumulating evidence clearly indicates that loss of global DNA methylation observed in cancer development and progression is tightly associated with hypomethylation of L1 elements. Significant progress achieved in the last several years suggests that such parameters as L1 methylation status can be potentially utilized as clinical biomarkers for determination of the disease stage and in predicting the disease-free survival in cancer patients. In this paper, we summarize the current knowledge on L1 methylation, with specific emphasis given to success and challenges on the way of introduction of L1 into clinical practice.

Re-Evaluating Disease-Free Survival as an Endpoint vs Overall Survival in Stage III Adjuvant Colon Cancer Trials

2021 ◽  
Author(s):  
Jun Yin ◽  
Mohamed E Salem ◽  
Jesse G Dixon ◽  
Zhaohui Jin ◽  
Romain Cohen ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Overall Survival ◽  
Disease Free Survival ◽  
Surrogate Endpoint ◽  
Free Survival ◽  
A Value ◽  
Deficient Mismatch Repair ◽  
Disease Free

Abstract Background Disease-free survival with a 3-year median follow-up (3-year DFS) was validated as a surrogate for overall survival with a 5-year median follow-up (5-year OS) in adjuvant chemotherapy colon cancer (CC) trials. Recent data show further improvements in OS and survival after recurrence, in patients who received adjuvant FOLFOX. Hence, re-evaluation of the association between DFS and OS and determination of the optimal follow-up duration of OS to aid its utility in future adjuvant trials are needed. Methods Individual patient data from nine randomized studies conducted between 1998 and 2009 were included; three trials tested biologics. Trial-level surrogacy examining the correlation of treatment effect estimates of 3-year DFS with 5 to 6.5-year OS was evaluated using both linear regression (R2WLS) and Copula bivariate (R2Copula) models and reported with 95% confidence intervals (CIs). For R2, a value closer to 1 indicates a stronger correlation. Results Data from a total of 18,396 patients were analyzed (median age = 59 years; 54.0% male), with 54.1% having low-risk tumors (pT1-3 & pN1), 31.6% KRAS mutated, 12.3% BRAF mutated, and 12.4% microsatellite instability high/deficient mismatch repair tumors. Trial level correlation between 3-year DFS and 5-year OS remained strong (R2 =0.82, 95% CI = 0.67 to 0.98; R2 =0.92, 95% CI = 0.83 to 1.00) and increased as the median follow-up of OS extended. Analyses limited to trials that tested biologics showed consistent results. Conclusion Three-year DFS remains a validated surrogate endpoint for 5-year OS in adjuvant CC trials. The correlation was likely strengthened with 6 years of follow-up for OS.

Pelvic Irradiation With Concurrent Chemotherapy Versus Pelvic and Para-Aortic Irradiation for High-Risk Cervical Cancer: An Update of Radiation Therapy Oncology Group Trial (RTOG) 90-01

2004 ◽  
Vol 22 (5) ◽  
pp. 872-880 ◽  
Author(s):  
Patricia J. Eifel ◽  
Kathryn Winter ◽  
Mitchell Morris ◽  
Charles Levenback ◽  
Perry W. Grigsby ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Overall Survival ◽  
Survival Rate ◽  
Locally Advanced ◽  
Disease Free Survival ◽  
Disease Stage ◽  
Tumor Diameter ◽  
Free Survival ◽  
Stage Ib ◽  
Disease Free

Purpose To report mature results of a randomized trial that compared extended-field radiotherapy (EFRT) versus pelvic radiotherapy with concomitant fluorouracil and cisplatin (CTRT) in women with locoregionally advanced carcinomas of the uterine cervix. Patients and Methods Four hundred three women with cervical cancer were randomly assigned to receive either EFRT or CTRT. Patients were eligible if they had stage IIB to IVA disease, stage IB to IIA disease with a tumor diameter ≥ 5 cm, or positive pelvic lymph nodes. Patients were stratified by stage and by method of lymph node evaluation. Results The median follow-up time for 228 surviving patients was 6.6 years. The overall survival rate for patients treated with CTRT was significantly greater than that for patients treated with EFRT (67% v 41% at 8 years; P < .0001). There was an overall reduction in the risk of disease recurrence of 51% (95% CI, 36% to 66%) for patients who received CTRT. Patients with stage IB to IIB disease who received CTRT had better overall and disease-free survival than those treated with EFRT (P < .0001); 116 patients with stage III to IVA disease had better disease-free survival (P = .05) and a trend toward better overall survival (P = .07) if they were randomly assigned to CTRT. The rate of serious late complications of treatment was similar for the two treatment arms. Conclusion Mature analysis confirms that the addition of fluorouracil and cisplatin to radiotherapy significantly improved the survival rate of women with locally advanced cervical cancer without increasing the rate of late treatment-related side effects.

Comparison of DNA Methylation and Expression Status Prior Azacytidine Treatment and their Relationship to Overall Survival and Clinical Response of MDS Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3777-3777
Author(s):  
Monika Belickova ◽  
Anna T Jonasova ◽  
Jitka Vesela ◽  
Eliska Stara ◽  
Andrea Hrustincova ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Overall Survival ◽  
Clinical Response ◽  
Partial Remission ◽  
Methylation Status ◽  
Prognostic Impact ◽  
Aberrant Expression ◽  
Hematopoietic Stem ◽  
Cd34 Cells ◽  
Expression Status

Abstract Background Myelodysplastic syndromes (MDS) are clonal disorders of hematopoietic stem cells characterized by ineffective hematopoiesis. High-risk MDS patients are treated by hypomethylating agents, of which they benefit significantly. However, only half of the patients respond positively to the treatment. Aberrant DNA methylation and mRNA expression in MDS were documented in several studies, but their prognostic impact in response to hypomethylating therapy is still unclear. The aim of the project was to find a relationship between methylation and expression status prior to azacytidine (AZA) treatment and the overall survival and clinical response of MDS patients. Methods We performed methylation and expression profiling in CD34+ cells from 30 samples from MDS patients before AZA treatment and after 4-8 treatment cycles. HumanMethylation27 BeadChips and HumanHT-12 v4 Expression BeadChips (Illumina) were used to generate profiles. DNA and RNA were isolated from same CD34+ cells separated from bone marrow by magnetic beads. The β-values represent quantitative measurements of DNA methylation levels of specific CpGs, and range from 0 for completely unmethylated to 1 for completely methylated DNA. The nonparametric Mann-Whitney test was used for comparison of β-values and expression levels between responders and nonresponders. Results To determine whether DNA methylation and expression might predict a response to AZA treatment, we compared methylation and expression status at baseline with clinical responses in 30 MDS patients. Twelve patients of 30 (40%) achieved complete remission or partial remission, 10 had stable disease (33.3%), and 8 showed progression (26.7%). Median survival after initiation of AZA treatment in progression patient group was 8.7 months, stable group 21.2 months, and group with complete or partial remission 24.5 months. We found significant differences in methylation status in 20 genes (p<0.05) between groups of responders and nonresponders and the largest methylation differences showed CALCA (0.61 vs. 0.16, p<0.05), MAGEE2 (0.71 vs. 0.30, p<0.05), HMP19 (0.62 vs. 0.23, p<0.05), MEOX1 (0.36 vs. 0.84, p<0.05), and KCNQ1DN genes (0.33 vs. 0.84, p<0.05). The aberrant expression status did not correlate with the response to AZA. We also measured methylation changes caused by AZA treatment. In the group of patients with progression, we did not find any change in the methylation profile after treatment. On the contrary, we found significant methylation changes after AZA treatment in the group of patients responding to treatment (e.g. AMT, NOTCH, and WT1genes). Conclusions Our finding of different DNA methylation levels at baseline between groups of responders and nonresponders as well as detection of decreased methylation after AZA treatment in the group of patients with clinical response may represent useful prediction markers of treatment success. However, the data require detailed examination along with confirmative cohort of patients. Supported by grant (NT/13899, NT/14377, NT/14539, NT/13847) and the project for conceptual development of research organization (00023736) from the Ministry of Health of the Czech Republic. Disclosures: No relevant conflicts of interest to declare.

Additional variables other than AJCC staging show clinical utility for predicting survival in colon cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14584-14584
Author(s):  
S. M. Wiseman ◽  
S. Leung ◽  
O. Griffith ◽  
S. Jones ◽  
H. Masoudi ◽  
...  
Keyword(s):  
Colon Cancer ◽  
Lymph Nodes ◽  
Disease Free Survival ◽  
Lymphatic Invasion ◽  
Disease Stage ◽  
Clinicopathologic Characteristics ◽  
Cancer Specific Survival ◽  
Free Survival ◽  
The Mean ◽  
Disease Free

14584 Background: The most important predictor of colon cancer patient outcome is disease stage at the time of surgery. However, staging does not accurately predict survival for all patients undergoing a resection with curative intent. The aim of this study was to analyze clinical and pathological characteristics of patients undergoing curative colon cancer, in order to identify characteristics, in addition to stage, predictive of disease outcome. Methods: Between 1997 and 2005 data for 114 patients undergoing curative resection for colon cancer at a tertiary care institution were collected. Clinical and pathological characteristics evaluated were: age, gender, tumor location, tumor size, scheduled vs emergent surgery, pathologic margin status, TNM stage, pathologic grade, number of positive lymph nodes, total number of lymph nodes resected, vascular and lymphatic invasion. Characteristics found to be significant in a Kaplan-Meier univariate survival analysis were included in a multivariate stepwise logistic regression analysis. Patient outcomes studied were overall survival, cancer specific survival, and disease free survival. Results: From the 114 patients examined in this cohort the mean age was 67 years, the male to female ratio was 0.8:1, and the mean follow up time was 2.61 years. Overall survival, cancer specific survival, and disease free survival were calculated to be 83.3%, 91.2% and 84.2%, respectively. Statistically significant variables by univariate analysis were: AJCC stage, number of positive lymph nodes, pathologic N stage, lymphatic and vascular invasion by the primary tumor. Further multivariate analysis revealed that lymphatic invasion was the only significant independent influence for predicting disease recurrence. Conclusions: Clinicopathologic characteristics, in addition to AJCC disease stage, may be of clinical utility in predicting outcome for patients who have undergone curative resection for colon cancer. Further evaluation of these clinicopathologic characteristics should be carried out in a larger colon cancer patient cohort. No significant financial relationships to disclose.

Phase III study of perioperative pembrolizumab (pembro) plus neoadjuvant chemotherapy (chemo) versus placebo plus neoadjuvant chemo in cisplatin-eligible patients (pts) with muscle-invasive bladder cancer (MIBC): KEYNOTE-866.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS599-TPS599 ◽  
Author(s):  
Arlene O. Siefker-Radtke ◽  
Gary D. Steinberg ◽  
Jens Bedke ◽  
Hiroyuki Nishiyama ◽  
Xiao Fang ◽  
...  
Keyword(s):  
Pathologic Complete Response ◽  
Disease Free Survival ◽  
Complete Response ◽  
Phase Iii ◽  
Disease Stage ◽  
End Points ◽  
Free Survival ◽  
Investigation Methods ◽  
Muscle Invasive ◽  
Pathway Inhibition

TPS599 Background: MIBC prognosis is poor, despite standard neoadjuvant cisplatin-based chemo. PD-1/PD-L1 pathway inhibition is an effective first-line option for cisplatin-ineligible pts and a second-line option for platinum-based chemo pretreated pts. Neoadjuvant chemo + pembro, a PD-1 inhibitor, recently showed encouraging pathologic complete response rates, in cisplatin-eligible patients with MIBC (NCT02365766), warranting further investigation. Methods: KEYNOTE-866 (NCT03924856) is a randomized phase 3 study to assess efficacy and safety of chemo+perioperative pembro versus chemo+perioperative placebo for pts with MIBC. An estimated 790 patients will be randomly assigned 1:1 to neoadjuvant pembro+chemo (4 cycles) followed by adjuvant pembro after radical cystectomy+pelvic lymph node dissection (RC+PLND, 13 cycles) or neoadjuvant placebo+chemo (4 cycles) followed by adjuvant placebo after RC+PLND (13 cycles). Pts will receive neoadjuvant and adjuvant pembro 200 mg IV Q3W; neoadjuvant chemo will be gemcitabine 1000 mg/m2+cisplatin 70 mg/m2 IV Q3W. Pts will be stratified by tumor PD-L1 status (combined positive score [CPS] ≥10 vs CPS <10), disease stage (T2 vs T3/4), and region of treatment (Unites States vs Europe vs most of world). Adults (≥18 y) with histologically confirmed MIBC (T2-T4aN0M0) who are cisplatin-eligible, are clinically nonmetastatic (N0M0), and have an ECOG PS 0 or 1 will be enrolled. Pts are required to provide tumor tissue for histology and PD-L1 analysis. Pts will not be permitted to have previously received systemic antineoplastic treatment for MIBC or radiotherapy to the bladder. Imaging by CT/MRI will be performed Q12W for up to 96 wk after cystectomy, at discontinuation, and during follow-up starting at 3 y (Q24W). Primary end points are pathologic complete response and event-free survival in all pts and pts with PD-L1 CPS ≥10. Secondary end points are OS, disease-free survival, and pathologic downstaging rate in all pts and pts with PD-L1 CPS ≥10, and safety. Accrual began June 13, 2019. Clinical trial information: NCT03924856.

scholarly journals FGFR4 Gly388Arg Polymorphism Reveals a Poor Prognosis, Especially in Asian Cancer Patients: A Meta-Analysis

2021 ◽  
Vol 11 ◽  
Author(s):  
Jung Han Kim ◽  
Soo Young Jeong ◽  
Hyun Joo Jang ◽  
Sung Taek Park ◽  
Hyeong Su Kim
Keyword(s):  
Cancer Patients ◽  
Transmembrane Domain ◽  
Meta Analysis ◽  
Disease Free Survival ◽  
Disease Stage ◽  
Prognostic Impact ◽  
Free Survival ◽  
Patients With Cancer ◽  
Ovid Medline ◽  
Hazard Ratios

The fibroblast growth factor-4 receptor (FGFR4) is a member of receptor tyrosine kinase. The FGFR4 Gly388Arg polymorphism in the transmembrane domain of the receptor has been shown to increase genetic susceptibility to cancers. However, its prognostic impact in cancer patients still remains controversial. Herein, we performed this meta-analysis to evaluate the clinicopathological and prognostic impacts of the FGFR4 Gly388Arg polymorphism in patients with cancer. We carried out a computerized extensive search using PubMed, Medline, and Ovid Medline databases up to July 2021. From 44 studies, 11,574 patients were included in the current meta-analysis. Regardless of the genetic models, there was no significant correlation of the FGFR4 Gly388Arg polymorphism with disease stage 3/4. In the homozygous model (Arg/Arg vs. Gly/Gly), the Arg/Arg genotype tended to show higher rate of lymph node metastasis compared with the Gly/Gly genotype (odds ratio = 1.21, 95% confidence interval (CI): 0.99-1.49, p = 0.06). Compared to patients with the Arg/Gly or Arg/Arg genotype, those with the Gly/Gly genotype had significantly better overall survival (hazard ratios (HR) = 1.19, 95% CI: 1.05-1.35, p = 0.006) and disease-free survival (HR = 1.25, 95% CI: 1.03-1.53, p = 0.02). In conclusion, this meta-analysis showed that the FGFR4 Gly388Arg polymorphism was significantly associated with worse prognosis in cancer patients. Our results suggest that this polymorphism may be a valuable genetic marker to identify patients at higher risk of recurrence or mortality.

scholarly journals Identification of a DNA methylation signature to predict disease-free survival in locally advanced rectal cancer

Oncotarget ◽  
2014 ◽  
Vol 5 (18) ◽  
pp. 8123-8135 ◽  
Author(s):  
Jochen Gaedcke ◽  
Andreas Leha ◽  
Rainer Claus ◽  
Dieter Weichenhan ◽  
Klaus Jung ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Rectal Cancer ◽  
Locally Advanced ◽  
Disease Free Survival ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Free Survival ◽  
Disease Free

scholarly journals Analysis of the clinical significance of DNA methylation in gastric cancer based on a genome-wide high-resolution array

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Wen-Liang Fang ◽  
Ming-Huang Chen ◽  
Kuo-Hung Huang ◽  
Shih-Ching Chang ◽  
Chien-Hsing Lin ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Dna Methylation ◽  
Disease Free Survival ◽  
Plasma Samples ◽  
Free Survival ◽  
Genome Wide ◽  
A Genome ◽  
Disease Free Survival Rate ◽  
Disease Free ◽  
Hypermethylated Genes

Abstract Background Aberrant DNA methylation is involved in gastric carcinogenesis and may serve as a useful biomarker in the diagnosis and detection of gastric cancer (GC) recurrence. Results A total of 157 patients who received surgery for GC were enrolled in the present study. A genome-wide methylation analysis was performed in tumor and adjacent normal tissues for the discovery set of 16 GC patients; the top three hypermethylated CpG sites of DNA promoters were selected for validation in tissue and plasma samples for the validation set of 141 GC patients. The frequencies of the top three hypermethylated genes in available patient tissues (n = 141) and plasma samples (n = 106) were 41.8% and 38.7%, respectively, for ADAM19; 40.4% and 42.5%, respectively, for FLI1; and 56.7% and 50.9%, respectively, for MSC. In both tissue and plasma samples, FLI1 hypermethylation was associated with more advanced GC and liver and distant lymphatic metastasis, and ADAM19 hypermethylation was associated with more stage IV GC. In plasma samples, MSC hypermethylation was more common in non-superficial type GC than samples without MSC hypermethylation. In both tissue and plasma samples, patients with methylation of all the three genes had significantly more liver metastases, distant lymphatic metastases, and paraaortic lymph node metastases than patients with two or fewer hypermethylated genes. The survival analysis showed that only for stage III GC, patients with hypermethylation of two or three genes had a worse 5-year disease-free survival rate than those with hypermethylation of one or none of the three genes. Subgroup analysis showed that FLI1 hypermethylation in both tissue and plasma samples was associated with liver metastasis in MSI−/EBV− GC, and MSC hypermethylation in tissue samples was correlated with liver metastasis in MSI+ or EBV+ GC. Patients with FLI1 hypermethylation in plasma samples had a significantly worse 5-year disease-free survival rate than those without FLI1 hypermethylation in MSI−/EBV− GC. FLI1 hypermethylation was an independent prognostic factor affecting the overall survival and disease-free survival in both tissue and plasma samples. Conclusions DNA methylation is a useful biomarker for predicting tumor recurrence patterns and GC patient survival.

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